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IMMUNOBIOLOGY
From the Section of Infection and Immunity, University
of Wales College of Medicine, Cardiff, United Kingdom, and the Imperial
College School of Medicine, London, United Kingdom.
Dendritic cells (DCs) play a pivotal role in the generation
of virus-specific cytotoxic T-cell responses, but some viruses can
render DCs inefficient in stimulating T cells. We studied whether
infection of DCs with human cytomegalovirus (HCMV) results in a
suppression of DC function which may assist HCMV in establishing persistence. The effect of HCMV infection on the phenotype and function
of monocyte-derived DCs and on their ability to mature following
infection with an endothelial cell-adapted clinical HCMV isolate were
studied. HCMV infection induced no maturation of DCs; instead, it
efficiently down-regulated the expression of surface major
histocompatibility complex (MHC) class I, CD40, and CD80 molecules.
Slight down-regulation of MHC class II and CD86 molecules was also
observed. Lipopolysaccharide (LPS)-induced maturation of infected DCs
was strongly inhibited, as indicated by lower levels of surface
expression of MHC class I, class II, costimulatory, and CD83 molecules.
The down-regulation or inhibition of these surface markers occurred
only in HCMV antigen-positive DCs. DCs produced no interleukin 12 (IL-12) and only low levels of tumor necrosis factor alpha (TNF- Dendritic cells (DCs) are the most potent
professional antigen-presenting cells (APCs) playing a central and
unique role in the generation of primary T-cell responses.
Whereas virus infections in general stimulate DC maturation and
lead to the generation of efficient antiviral T-cell responses, some
viruses have developed mechanisms to interfere with the normal functions of DCs. Human immunodeficiency virus (HIV), measles virus,
herpes simplex virus-1 (HSV-1), and vaccinia virus, for example, are
all known to cause defects in DC maturation and function which
consequently lead to impaired antiviral T-cell
responses.1-4
The major risk factor for HCMV infection in bone marrow
transplant patients is their pre-existing seropositive
status.5 Delayed reconstitution of the antiviral cellular
immune response in these patients is often associated with HCMV
infection and progressive disease with poor prognosis. CD8+
T cells are the main cell type controlling HCMV infection as proven by
their successful adoptive transfer preventing viraemia and HCMV disease
in bone marrow transplant recipients.6 HCMV infection is
also associated with serious secondary bacterial or fungal infections
in immunosuppressed patients,7,8 although during the early
phase of acute HCMV infection, transiently suppressed cellular immune
responses9,10 and immunologic abnormalities of healthy
individuals11 were also reported. HCMV has been shown to
interfere with antigen presentation in fibroblasts and endothelial cells12 by (1) expressing viral proteins which interfere
with the MHC class I antigen-presenting pathways (US3, US2, US11); (2)
modulating antigen procession of the HCMV immediate early 1 (IE1)
protein (pp65); and (3) preventing peptide transport through TAP
proteins (US6). However, little is known about whether the induction
phase of HCMV-specific T-cell responses is also affected. From the few
studies that looked at HCMV infection of monocytes, macrophages, and
DCs,13-15 only one seemed to establish a link between HCMV
infection of macrophages and impaired proliferation of CD4+
T cells upon stimulation with these macrophages.15
We hypothesized that similar to its effects in fibroblasts and
endothelial cells, HCMV also inhibits the expression of MHC class I
molecules in DCs. Although this inhibitory effect alone would probably
be sufficient to prevent or impair the generation of virus-specific
primary T-cell responses, other important features such as the
expression of costimulatory molecules, the production of
proinflammatory cytokines, and the antigen-presenting function of
monocyte-derived DCs were also studied following HCMV infection. We
show that HCMV impairs all these properties of DCs. The viral inhibition may contribute not only to the successful establishment of
latency by HCMV but also to the immunosuppression observed in
association with the infection.
Donors
Cell lines and tissue culture reagents
Viruses HCMVTB40/E is an endothelial cell-adapted HCMV strain isolated from a bone marrow transplant recipient. It was kindly provided by Dr Christian Sinzger (Tübingen, Germany).17 HFFs were grown to about 90% confluence and infected with a low multiplicity of infection (MOI) (0.1-1 plaque-forming unit [PFU]/cell) of HCMVTB40/E in 4 mL of MEM for 1 to 2 hours at 37°C. The virus was then removed and the cells cultured in MEM plus 10% FCS until the first cytopathic effects appeared (4-7 days). Supernatants of infected HFFs were collected daily, or every second day, until the cytopathic effects became advanced. Supernatants were centrifuged at 1200g for 10 minutes to remove cells and debris and the supernatant was stored at 70°C in small aliquots. In some experiments a concentrated virus
stock was used which was obtained from cell-free supernatant by
ultracentrifugation at 80 000g for 70 minutes at room
temperature in a Beckman L8-M ultracentrifuge using an SW41 rotor
(Beckman Instruments, Fullerton, CA). The pellet containing
viral particles from 20 mL supernatant was resuspended in 1 mL complete
RPMI. Viral titres, determined from the TCID50
values (dilution of virus required to infect 50% of cultures) on HFF
cells, grown in 48-well plates for 2 to 3 weeks, varied between
5 × 106/mL and 5 × 108/mL.
HCMVTB40/E was inactivated at room temperature by a
2-minute UV irradiation (253 nm, 30 W/G30 T8 tube by Philips,
Almelo, The Netherlands).
Influenza A (AX/31) virus was kindly provided by Dr D. B. Thomas and Dr J. Skehel (National Institute for Medical Research, London, United Kingdom). The virus has been grown in the allantoic cavity of embryonated chicken eggs. The viral hemagglutination titer, determined by chicken red cell agglutination, was 1000 hemagglutinating units (HAU)/50 µL. The cell lines and the virus stocks were negative for contamination with mycoplasma as determined by a mycoplasma PCR kit (VenorGem; Minerva Biolabs GmbH, Berlin, Germany). Generation and culture of monocyte-derived DCs PBMCs were isolated by Ficoll-Histopaque (Sigma) density gradient centrifugation of heparinized peripheral blood of healthy donors. DCs were generated from blood monocytes according to standard methods.18 Briefly, the adherent fraction of PBMCs was obtained after a 1 hour plastic adherence step (6-well plates, 15 × 106 PBMCs/well) (Nunc, Naperville, IL) in complete RPMI containing 1% FCS. The nonadherent cells were removed and the adherent cells were cultured in complete RPMI containing 10% FCS, 50 ng/mL human recombinant granulocyte macrophage-colony-stimulating factor (GM-CSF) (Leucomax; Novartis Pharmaceuticals, East Hanover, NJ) and 500 U/mL human recombinant IL-4 (BD Pharmingen, San Diego, CA). Nonadherent and loosely adherent DCs were collected and used in the experiments after 4 to 7 days in culture. More than 90% of the cells were of DC phenotype (CD1a+, HLA-DR+, CD14 , CD80+) after gating on size and side
scatter parameters by fluorescence activated cell sorting (FACS) to
exclude lymphocytes. Maturation of DCs was induced by 1 µg/mL LPS
(Sigma) in the presence of 100 ng/mL interferon gamma (IFN- )
(Peprotech, Rocky Hill, NJ) and 50 ng/mL TNF- (R&D, Minneapolis, MN)
at 0.5 × 106 to 1 × 106 DCs/mL in
complete RPMI containing 10% FCS.
Infection of DCs DCs were counted and either infected with HCMVTB40/E at MOI = 1-10 PFU/cell or mock infected with MEM plus 10% FCS for 3 hours or overnight as indicated in the figure legends. After removal of the virus or MEM, DCs were washed and cultured in complete RPMI containing 10% FCS and 50 ng/mL GM-CSF for a total of 24 or 48 hours. For infection with influenza, 105 DCs were incubated with 5 HAU influenza A (AX/31) in a total volume of 200 µL for 10 minutes on ice followed by 30 minutes at 37°C. DCs were washed once in serum-free complete RPMI and cultured in complete RPMI containing 10% AB serum (Sigma) for 6 hours before using them in the experiments.Flow cytometry To assess expression of surface molecules on DCs, 1 × 105 to 2 × 105 DCs were labeled for 40 minutes at 4°C with antibodies at 1 µg per sample or as recommended by the manufacturer. In order to detect viral antigens, intracellular staining of DCs, labeled as above for surface molecules or unlabeled, was carried out. DCs were fixed with 4% paraformaldehyde for 20 minutes at room temperature and permeabilized with 0.025% Triton X-100 for 20 minutes at room temperature. Nonspecific binding was blocked with 2% mouse serum for 10 minutes at room temperature followed by labeling with fluorescein isothiocyanate (FITC)- or phycoerythrin (PE)-conjugated antibodies for 1 hour at 37°C. Cytokine production by LPS-stimulated or infected DCs was detected by adding 1 µL/mL GolgiPlug (BD Pharmingen) to DCs 2 hours following infection or LPS treatment and culturing the cells for a further 18 to 20 hours. DCs were fixed, permeabilized, and blocked as above and HCMV pp52-FITC antibody was added together with either IL-12-PE or TNF--PE antibody for 1 hour at 37°C. The cells were analyzed on a
FACSCalibur (BD Pharmingen) using CellQuest 3.1 software. The following
antibodies were used for labeling: HCMV p52 early antigen-specific
FITC-conjugated antibody (CCH2; Dako, Carpinteria, CA), anti-MHC class
I/CyChrome, anti-HLA-DR/CyChrome, anti-CD80/CyChrome, anti-CD83/PE,
anti-IL-12/PE and anti-TNF-/PE (all from BD Pharmingen),
anti-CD86/TriColour and anti-CD120b (TNFRII, 75 kd)/RPE (Caltag,
Burlingame, CA), anti-CD40 (Diaclone, Besançon, France),
PE-conjugated mouse IgG1 (Immunotech, Luminy, France), and
PE-conjugated rabbit anti-mouse IgG F(ab')2 (STAR 12A;
Serotec, Oxford, United Kingdom).
Preparation of protein extracts and immunoblotting Immature DCs were either mock infected, infected with HCMVTB40E, or UV-irradiated HCMVTB40E was added. After 24 hours, the cells were either left unstimulated or were stimulated with LPS in the presence of IFN- and TNF-, as above,
for 24 hours. Cells were washed in phosphate-buffered saline. For
nuclear extracts the cell pellet of 3 × 105 to
5 × 105 DCs per group was lysed in nuclear extraction
buffer and an equal volume of 2x gel sample buffer was added to the
clarified lysate. The proteins were separated by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred
to polyvinylidenefluoride (PVDF) for immunoblotting using an alkaline
phosphatase chemiluminescent detection protocol. RelB and p50 were
detected using rabbit polyclonal antibodies, kindly provided by Dr
Nancy Rice (Frederick, MD). The polyclonal actin-specific
antibody was purchased from Sigma.
Generation of cytotoxic T lymphocytes in vitro, cytotoxicity and proliferation assays Nonadherent PBMCs were kept frozen in liquid N2 and later used as a T-cell source. T-cell stimulation was carried out in complete RPMI containing 10% AB serum (Sigma). DCs were either (1) infected with influenza for 6 hours; (2) infected with both HCMVTB40/E (total of 48 hours) and influenza (6 hours); or (3) mock infected as described earlier. T-cells were added to DCs at a ratio of 10:1 at the concentration of 1.5 × 106 nonadherent PBMCs plus 1.5 × 105 DCs per mL and cultured in 12-well trays at 3 mL/well for 7 days prior to testing the cytotoxic T lymphocyte (CTL) activity in a standard 51Cr-release assay. Autologous BLCs were used as target cells. They were labeled with 135 µCi (5 MBq) 51Cr/106 cells for 1 hour at 37°C. BLCs were washed twice and incubated either with 50 µM HLA-A2-restricted influenza M1 58-66 peptide in 5 µL dimethyl sulfoxide (DMSO) or with 5 µL/mL DMSO without peptide for another hour. Targets were plated out at 3 × 103 BLCs/well. T cells, cultured for 7 days with DCs, were washed, counted, and added at gradually decreasing numbers to target cells, starting at a 40:1 effector-target (E/T) ratio, in triplicates. The cells were incubated for 4 hours at 37°C in 200 µL final volume per well. A 25-µL aliquot of the supernatant from each well was transferred into wells of 96-well soft plates and mixed with 130 µL Betaplate scintillation fluid. Radioactivity was measured on a -plate counter (1450 Microbeta; Wallac, Milton-Keynes,
United Kingdom). The lysis of targets from each well was calculated as follows: (experimental release spontaneous release) / (maximum release spontaneous release) × 100, and expressed as percent specific lysis. Spontaneous release and maximum release of
51Cr were determined by incubating target cells either with
medium only or with 5% Triton X-100. T-cell proliferation was measured after stimulation of the nonadherent PBMCs with DCs generated and
infected as described above. A quantity of 105 autologous
nonadherent PBMCs per well was coincubated with 5 × 103,
2.5 × 103, 1.25 × 103,
6.25 × 102, or 3.1 × 102 DCs/well in
triplicates. 3H-thymidine (Amersham Pharmacia, Piscataway,
NJ) was added at 0.5 µCi/well (0.018 MBq) on day 5 of the
culture for 16 hours. The cells were harvested onto fibroglass
filtermats and 3H-thymidine incorporation was measured by a
Wallac 1450 Microbeta -plate counter.
Statistical analysis Statistical analysis was performed using the Student t test. Differences were considered statistically significant with P < .05.
HCMV infection does not induce maturation of DCs: the expression
of cell-surface molecules, especially that of MHC class I, CD40, and
CD80, is decreased on DCs following infection. Viral infections can
either induce or suppress the maturation and functional activation of
DCs. To study the effect of HCMV on DCs, we first compared the
expression of surface markers on DCs infected with HCMVTB40/E (Figure 1A, second
row) with that on mock-infected DCs (Figure 1A, first row). The
infection rate of DCs varied between 30% and 70% in the experiments
and thus it was necessary to analyze HCMV Ag-positive DCs (Figure 1A,
second row, right side of dot plots) separately from Ag-negative DCs
(Figure 1A, second row, left side of dot plots). The summary of results
from 3 to 4 repeated experiments (Figure 1B) shows that the relative
fluorescence intensity (RFI) of surface MHC class I molecules on
Ag-positive DCs is only 20% of that on mock-infected DCs. The RFI of
the expression of CD40 and CD80 molecules (Figure 1B) was also less
than 50%. The expression of MHC class II and CD86 molecules was also
weaker on Ag-positive than on mock-infected DCs, whereas CD83
expression was low on mock-infected DCs and remained low following
infection (Figure 1A). The level of expression of all the molecules
mentioned above was at least as high or higher on the Ag-negative DCs
(Figure 1A, second row, left side of dot plots) than on mock-infected DCs (Figure 1A, first row), indicating that in the absence of viral
infection bystander DC activation by binding of viral products or
soluble factors may occur. Higher level of TNFRII expression on
Ag-positive than on Ag-negative DCs indicated that the down-regulation of surface molecules was not due to a general shut-down of protein synthesis by the virus (data not shown).
HCMV infection of DCs inhibits LPS-induced DC maturation. As shown in
Figure 1, HCMV does not induce maturation of immature DCs, unlike, for
example, adenoviruses or dengue virus. The ability of immature DCs to
begin the differentiation process into mature DCs in response to
certain proinflammatory cytokines (TNF-
Mature DCs are relatively resistant to infection by HCMV. Immature DCs
capture antigens in the periphery, and during maturation DCs gradually
lose their ability to take up antigens by phagocytosis. However, they
still may be susceptible to viral infections which could impair DC
function. We mimicked this scenario by exposing DCs first to maturation
signals provided by LPS, TNF-
DCs produce no IL-12 and only low levels of TNF-
HCMV-infected DCs remain unresponsive to further stimulation to produce
cytokines. Some pathogens stimulate DCs to produce IL-12 with early
kinetics followed by a refractory period when DCs become unresponsive
to further stimulation to produce cytokines.21 This can
lead either to some degree of immunosuppression, similar to that
observed in IL-12R-deficient patients,22 or to protection of the host against the pathogenic events of prolonged
inflammation.21 On the other hand, interaction with
certain pathogens or with their products "conditions" DCs to be
susceptible to second signals such as T-cell encounter (DC40-CD40L
interaction) which then leads to the production of high levels of
IL-12.23 HCMV did not induce an early peak of IL-12
production and only a low level of TNF-
IL-12 and TNF- HCMV induces changes in the level of nuclear NF- T-cell proliferation and cytotoxicity are impaired following
stimulation with HCMV-infected DCs. The consequences of DC infection by
HCMV, such as interference with the expression of DC surface molecules
and inhibition of maturation and cytokine production, probably have the
main impact on the generation of primary antiviral T-cell responses. In
the absence of an in vitro model to prime naïve T cells, we
investigated whether HCMV-infected DCs were impaired in their ability
to induce MHC class I-mediated T-cell responses to a recall antigen in
vitro (Figure 6). Secondary
CD8+ T-cell responses do not require costimulation and thus
the outcome of such an experiment would mainly be influenced by the
down-regulation of MHC class I molecules on infected DCs. Immature DCs
from an HCMV seronegative donor were infected with
HCMVTB40/E (MOI = 10) for 48 hours and then incubated
with influenza virus for 6 hours prior to adding autologous T cells.
Influenza-specific T-cell proliferation at day 5 following stimulation
was reduced when HCMV-infected DCs were used as APCs, compared with
proliferation induced with mock infected DCs (Figure 6A). A
CTL assay, with T cells from day 7 cultures against M1 peptide-pulsed
autologous BLCL targets revealed that HCMV-infected DCs had a
much-reduced ability to stimulate cytotoxic T-cell responses to
influenza virus (Figure 6B, triangles) than did mock-infected DCs
(Figure 6B, circles), confirming that antigen presentation by DCs and
their ability to stimulate a secondary T-cell response are impaired following HCMV infection. The results for (A) and (B) are
representative of 3 similar experiments.
In this paper, we demonstrate that HCMV interferes with the
maturation and antigen-presenting function of DCs. Following HCMV infection of DCs in vitro, we observed down-regulation of MHC class I
molecules on immature and on LPS-treated DCs; inhibition of DC
maturation, as indicated by the lack of up-regulation of MHC class II
and costimulatory molecules (CD40, CD80, CD86) and CD83 on DCs;
impaired proinflammatory cytokine production (IL-12 and TNF- HCMV decreases the expression of MHC class I molecules on fibroblasts12 and on endothelial cells25 and partially downregulates surface expression of MHC class I molecules on human macrophages26 by multiple mechanisms. The finding of down-regulation of MHC class I molecules on DCs is in agreement with these studies. Our results indicate that MHC class I down-regulation is an important viral mechanism not only in avoiding CTL killing of infected target cells but also in inhibiting, or at least delaying, the generation of virus-specific primary T-cell responses. Constitutive MHC class II expression is restricted to B cells,
monocytes, and thymic epithelial cells, whereas IFN- This is the first study to examine the effect of HCMV infection on the
expression of costimulatory molecules on DCs. We demonstrate here that
HCMV infection causes down-regulation of CD40, CD80 and, to a lesser
extent, of CD86 molecules on immature DCs. Ligation of CD40 molecules
on DCs by the CD40L on T cells normally results in the terminal
differentiation of DCs. The interaction strongly increases the
expression of MHC class I, class II, and costimulatory molecules on DCs
and the production of cytokines (IL-12, TNF- The production of TNF- DCs represent an ideal target for pathogens because interference
with the maturation process and function of DCs can have severe and
multiple consequences for T-cell and B-cell responses. Measles virus is one of the best known examples. Although the virus
induces maturation of DCs,38 it inhibits IL-12 production by activated DCs, resulting in impaired capacity to stimulate T cells
and causing transient but profound immunosuppression.2 Other viruses, such as HSV-1 and vaccinia,3,4 inhibit the maturation of DCs, resulting in impaired development of efficient antiviral T-cell immunity. The severe secondary bacterial or fungal infections7,8 following acute HCMV infection in
immunosuppressed patients might be due to viral interference with DC
function. Our results show that HCMV-infected DCs do not mature upon
additional signals such as LPS and that there is a nearly complete
inhibition of IL-12 and TNF- The inhibition of DC maturation and function by HCMV and the low level of cell-surface expression of MHC class I molecules on DCs at any stage of their maturation seem to contradict the relatively high frequencies of T cells specific for HCMV antigens reported by several authors.40-43 Our previous report on cross-presentation of HCMV antigens by uninfected DCs to CD8+ T cells offers a likely explanation of how the immune system bypasses the inhibitory effects of HCMV.44 Our model described uninfected DCs acquiring viral antigens from infected fibroblasts, but it is probable that cross-presentation of viral antigens occurs between uninfected DCs and any infected cell, such as endothelial cells and even DCs. Cross-presentation may play a much more important role in the generation of virus-specific T-cell responses than previously thought. Down-regulation of MHC class I molecules and the inhibition of
up-regulation of maturation-associated molecules on DCs requires active
viral infection because UV-irradiated HCMV did not have any inhibitory
effect. Soluble inhibitory factors produced by the virus or by infected
DCs can also be excluded because HCMV Ag-negative DCs from cultures
containing infected DCs showed signs of bystander stimulation instead
of inhibition, probably due to phagocytosed viral particles and or
cellular debris. The search for viral genes responsible for the
observed inhibition of cell-surface molecule expression on DCs is
hampered by the fact that (1) the well-characterized laboratory strain
of HCMV (AD169), which is used extensively by virologists, does not
infect DCs17,44; and (2) recombinant adenovirus vectors,
which would be useful for HCMV gene expression studies, cause
maturation of DCs.45 The binding of HCMV or its purified
ligands (gB and gH) to monocytes was shown to be sufficient in
initiating nuclear translocation of NF- In summary, our study demonstrates the presence of an important viral evasion strategy by HCMV; namely, the impairment of the maturation and function of professional APCs. Interference with the stimulation of naïve and memory T cells specific for HCMV antigens is likely to aid HCMV to escape T-cell recognition, whereas impaired DC function against other pathogens may contribute to HCMV-associated immunosuppression.
We thank C. Sinzger for the TB40E strain of HCMV and for
stimulating discussions; N. Rice for the NF-
Submitted May 14, 2001; accepted December 4, 2001.
Supported by a University of Wales College of Medicine PhD scholarship to M.M., by the Leukaemia Research Fund to A.M.M., and by program grant 048665 from the Wellcome Trust to Z.T.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Zsuzsanna Tabi, Research Oncology Unit, Velindre Hospital, Whitchurch, Cardiff CF14 2TL, United Kingdom; e-mail: tabiz{at}cf.ac.uk.
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  R. Mittal, S. Bulgheresi, C. Emami, and N. V. Prasadarao Enterobacter sakazakii Targets DC-SIGN to Induce Immunosuppressive Responses in Dendritic Cells by Modulating MAPKs J. Immunol., November 15, 2009; 183(10): 6588 - 6599. [Abstract] [Full Text] [PDF]
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S. M. Hughes, B. Amadi, M. Mwiya, H. Nkamba, A. Tomkins, and D. Goldblatt Dendritic Cell Anergy Results from Endotoxemia in Severe Malnutrition J. Immunol., August 15, 2009; 183(4): 2818 - 2826. [Abstract] [Full Text] [PDF]
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S. Saghafian-Hedengren, Y. Sundstrom, E. Sohlberg, C. Nilsson, A. Linde, M. Troye-Blomberg, L. Berg, and E. Sverremark-Ekstrom Herpesvirus Seropositivity in Childhood Associates with Decreased Monocyte-Induced NK Cell IFN-{gamma} Production J. Immunol., February 15, 2009; 182(4): 2511 - 2517. [Abstract] [Full Text] [PDF]
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A. Saez-Borderias, N. Romo, G. Magri, M. Guma, A. Angulo, and M. Lopez-Botet IL-12-Dependent Inducible Expression of the CD94/NKG2A Inhibitory Receptor Regulates CD94/NKG2C+ NK Cell Function J. Immunol., January 15, 2009; 182(2): 829 - 836. [Abstract] [Full Text] [PDF]
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V. Bohm, C. O. Simon, J. Podlech, C. K. Seckert, D. Gendig, P. Deegen, D. Gillert-Marien, N. A. W. Lemmermann, R. Holtappels, and M. J. Reddehase The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation J. Virol., December 1, 2008; 82(23): 11637 - 11650. [Abstract] [Full Text] [PDF]
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S. Arimilli, J. B. Johnson, K. M. Clark, A. H. Graff, M. A. Alexander-Miller, S. B. Mizel, and G. D. Parks Engineered Expression of the TLR5 Ligand Flagellin Enhances Paramyxovirus Activation of Human Dendritic Cell Function J. Virol., November 15, 2008; 82(22): 10975 - 10985. [Abstract] [Full Text] [PDF]
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W. Dejnirattisai, T. Duangchinda, C.-L. S. Lin, S. Vasanawathana, M. Jones, M. Jacobs, P. Malasit, X.-n. Xu, G. Screaton, and J. Mongkolsapaya A Complex Interplay among Virus, Dendritic Cells, T Cells, and Cytokines in Dengue Virus Infections J. Immunol., November 1, 2008; 181(9): 5865 - 5874. [Abstract] [Full Text] [PDF]
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S. Munir, C. Le Nouen, C. Luongo, U. J. Buchholz, P. L. Collins, and A. Bukreyev Nonstructural Proteins 1 and 2 of Respiratory Syncytial Virus Suppress Maturation of Human Dendritic Cells J. Virol., September 1, 2008; 82(17): 8780 - 8796. [Abstract] [Full Text] [PDF]
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L. A. Smyth, N. Harker, W. Turnbull, H. El-Doueik, L. Klavinskis, D. Kioussis, G. Lombardi, and R. Lechler The Relative Efficiency of Acquisition of MHC:Peptide Complexes and Cross-Presentation Depends on Dendritic Cell Type J. Immunol., September 1, 2008; 181(5): 3212 - 3220. [Abstract] [Full Text] [PDF]
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M. J. Raftery, M. Hitzler, F. Winau, T. Giese, B. Plachter, S. H. E. Kaufmann, and G. Schonrich Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus J. Virol., May 1, 2008; 82(9): 4308 - 4319. [Abstract] [Full Text] [PDF]
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C. Jenkins, W. Garcia, M. J. Godwin, J. V. Spencer, J. L. Stern, A. Abendroth, and B. Slobedman Immunomodulatory Properties of a Viral Homolog of Human Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection J. Virol., April 1, 2008; 82(7): 3736 - 3750. [Abstract] [Full Text] [PDF]
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C. A. Benedict, A. Loewendorf, Z. Garcia, B. R. Blazar, and E. M. Janssen Dendritic Cell Programming by Cytomegalovirus Stunts Naive T Cell Responses via the PD-L1/PD-1 Pathway J. Immunol., April 1, 2008; 180(7): 4836 - 4847. [Abstract] [Full Text] [PDF]
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M. Mandron, H. Martin, B. Bonjean, J. Lule, E. Tartour, and C. Davrinche Dendritic cell-induced apoptosis of human cytomegalovirus-infected fibroblasts promotes cross-presentation of pp65 to CD8+ T cells J. Gen. Virol., January 1, 2008; 89(1): 78 - 86. [Abstract] [Full Text] [PDF]
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S. Varani, M. Cederarv, S. Feld, C. Tammik, G. Frascaroli, M. P. Landini, and C. Soderberg-Naucler Human Cytomegalovirus Differentially Controls B Cell and T Cell Responses through Effects on Plasmacytoid Dendritic Cells J. Immunol., December 1, 2007; 179(11): 7767 - 7776. [Abstract] [Full Text] [PDF]
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R. Hochreiter, C. Ptaschinski, S. L. Kunkel, and R. Rochford Murine gammaherpesvirus-68 productively infects immature dendritic cells and blocks maturation J. Gen. Virol., July 1, 2007; 88(7): 1896 - 1905. [Abstract] [Full Text] [PDF]
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C. Molle, M. Nguyen, V. Flamand, J. Renneson, F. Trottein, D. De Wit, F. Willems, M. Goldman, and S. Goriely IL-27 Synthesis Induced by TLR Ligation Critically Depends on IFN Regulatory Factor 3 J. Immunol., June 15, 2007; 178(12): 7607 - 7615. [Abstract] [Full Text] [PDF]
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E. J. Wiertz, R. Devlin, H. L. Collins, and M. E. Ressing Herpesvirus Interference with Major Histocompatibility Complex Class II-Restricted T-Cell Activation J. Virol., May 1, 2007; 81(9): 4389 - 4396. [Full Text] [PDF]
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J. D. Mintern, E. J. Klemm, M. Wagner, M. E. Paquet, M. D. Napier, Y. M. Kim, U. H. Koszinowski, and H. L. Ploegh Viral Interference with B7-1 Costimulation: A New Role for Murine Cytomegalovirus Fc Receptor-1 J. Immunol., December 15, 2006; 177(12): 8422 - 8431. [Abstract] [Full Text] [PDF]
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A. N. Harman, J. Wilkinson, C. R. Bye, L. Bosnjak, J. L. Stern, M. Nicholle, J. Lai, and A. L. Cunningham HIV Induces Maturation of Monocyte-Derived Dendritic Cells and Langerhans Cells J. Immunol., November 15, 2006; 177(10): 7103 - 7113. [Abstract] [Full Text] [PDF]
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A. W. Lee, L. Hertel, R. K. Louie, T. Burster, V. Lacaille, A. Pashine, D. A. Abate, E. S. Mocarski, and E. D. Mellins Human Cytomegalovirus Alters Localization of MHC Class II and Dendrite Morphology in Mature Langerhans Cells J. Immunol., September 15, 2006; 177(6): 3960 - 3971. [Abstract] [Full Text] [PDF]
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 K.-D. Park, L. Marti, J. Kurtzberg, and P. Szabolcs In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T cells from naive cord blood lymphocytes Blood, September 1, 2006; 108(5): 1770 - 1773. [Abstract] [Full Text] [PDF]
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G. Frascaroli, S. Varani, B. Moepps, C. Sinzger, M. P. Landini, and T. Mertens Human cytomegalovirus subverts the functions of monocytes, impairing chemokine-mediated migration and leukocyte recruitment. J. Virol., August 1, 2006; 80(15): 7578 - 7589. [Abstract] [Full Text] [PDF]
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G. Frascaroli, S. Varani, A. Mastroianni, S. Britton, D. Gibellini, G. Rossini, M. P. Landini, and C. Soderberg-Naucler Dendritic cell function in cytomegalovirus-infected patients with mononucleosis J. Leukoc. Biol., May 1, 2006; 79(5): 932 - 940. [Abstract] [Full Text] [PDF]
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S. Arimilli, M. A. Alexander-Miller, and G. D. Parks A Simian Virus 5 (SV5) P/V Mutant Is Less Cytopathic than Wild-Type SV5 in Human Dendritic Cells and Is a More Effective Activator of Dendritic Cell Maturation and Function. J. Virol., April 1, 2006; 80(7): 3416 - 3427. [Abstract] [Full Text] [PDF]
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E. O. Kvale, J. Dalgaard, F. Lund-Johansen, H. Rollag, L. Farkas, K. Midtvedt, F. L. Jahnsen, J. E. Brinchmann, and J. Olweus CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection Blood, March 1, 2006; 107(5): 2022 - 2029. [Abstract] [Full Text] [PDF]
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C. M. Bosio and S. W. Dow Francisella tularensis Induces Aberrant Activation of Pulmonary Dendritic Cells J. Immunol., November 15, 2005; 175(10): 6792 - 6801. [Abstract] [Full Text] [PDF]
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H. Barth, A. Ulsenheimer, G. R. Pape, H. M. Diepolder, M. Hoffmann, C. Neumann-Haefelin, R. Thimme, P. Henneke, R. Klein, G. Paranhos-Baccala, et al. Uptake and presentation of hepatitis C virus-like particles by human dendritic cells Blood, May 1, 2005; 105(9): 3605 - 3614. [Abstract] [Full Text] [PDF]
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A. P. Smith, C. Paolucci, G. Di Lullo, S. E. Burastero, F. Santoro, and P. Lusso Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6 J. Virol., March 1, 2005; 79(5): 2807 - 2813. [Abstract] [Full Text] [PDF]
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G. Gerna, E. Percivalle, D. Lilleri, L. Lozza, C. Fornara, G. Hahn, F. Baldanti, and M. G. Revello Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen presentation to CD8+ T cells J. Gen. Virol., February 1, 2005; 86(2): 275 - 284. [Abstract] [Full Text] [PDF]
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S. Varani, G. Frascaroli, M. Homman-Loudiyi, S. Feld, M. P. Landini, and C. Soderberg-Naucler Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5 J. Leukoc. Biol., February 1, 2005; 77(2): 219 - 228. [Abstract] [Full Text] [PDF]
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A. Loewendorf, C. Kruger, E. M. Borst, M. Wagner, U. Just, and M. Messerle Identification of a Mouse Cytomegalovirus Gene Selectively Targeting CD86 Expression on Antigen-Presenting Cells J. Virol., December 1, 2004; 78(23): 13062 - 13071. [Abstract] [Full Text] [PDF]
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A. Smed-Sorensen, K. Lore, L. Walther-Jallow, J. Andersson, and A.-L. Spetz HIV-1-infected dendritic cells up-regulate cell surface markers but fail to produce IL-12 p70 in response to CD40 ligand stimulation Blood, November 1, 2004; 104(9): 2810 - 2817. [Abstract] [Full Text] [PDF]
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M. J. Raftery, D. Wieland, S. Gronewald, A. A. Kraus, T. Giese, and G. Schonrich Shaping Phenotype, Function, and Survival of Dendritic Cells by Cytomegalovirus-Encoded IL-10 J. Immunol., September 1, 2004; 173(5): 3383 - 3391. [Abstract] [Full Text] [PDF]
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W. L. W. Chang, N. Baumgarth, D. Yu, and P. A. Barry Human Cytomegalovirus-Encoded Interleukin-10 Homolog Inhibits Maturation of Dendritic Cells and Alters Their Functionality J. Virol., August 15, 2004; 78(16): 8720 - 8731. [Abstract] [Full Text] [PDF]
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F. Goodrum, C. T. Jordan, S. S. Terhune, K. High, and T. Shenk Differential outcomes of human cytomegalovirus infection in primitive hematopoietic cell subpopulations Blood, August 1, 2004; 104(3): 687 - 695. [Abstract] [Full Text] [PDF]
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B. Senechal, A. M. Boruchov, J. L. Reagan, D. N. J. Hart, and J. W. Young Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83 Blood, June 1, 2004; 103(11): 4207 - 4215. [Abstract] [Full Text] [PDF]
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M. Moutaftsi, P. Brennan, S. A. Spector, and Z. Tabi Impaired Lymphoid Chemokine-Mediated Migration due to a Block on the Chemokine Receptor Switch in Human Cytomegalovirus-Infected Dendritic Cells J. Virol., March 15, 2004; 78(6): 3046 - 3054. [Abstract] [Full Text] [PDF]
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W. Tu, S. Chen, M. Sharp, C. Dekker, A. M. Manganello, E. C. Tongson, H. T. Maecker, T. H. Holmes, Z. Wang, G. Kemble, et al. Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children J. Immunol., March 1, 2004; 172(5): 3260 - 3267. [Abstract] [Full Text] [PDF]
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P. Sarobe, J. J. Lasarte, A. Zabaleta, L. Arribillaga, A. Arina, I. Melero, F. Borras-Cuesta, and J. Prieto Hepatitis C Virus Structural Proteins Impair Dendritic Cell Maturation and Inhibit In Vivo Induction of Cellular Immune Responses J. Virol., October 15, 2003; 77(20): 10862 - 10871. [Abstract] [Full Text] [PDF]
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S. Gredmark and C. Soderberg-Naucler Human Cytomegalovirus Inhibits Differentiation of Monocytes into Dendritic Cells with the Consequence of Depressed Immunological Functions J. Virol., October 15, 2003; 77(20): 10943 - 10956. [Abstract] [Full Text] [PDF]
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X. Wang, M. Messerle, R. Sapinoro, K. Santos, P. K. Hocknell, X. Jin, and S. Dewhurst Murine Cytomegalovirus Abortively Infects Human Dendritic Cells, Leading to Expression and Presentation of Virally Vectored Genes J. Virol., July 1, 2003; 77(13): 7182 - 7192. [Abstract] [Full Text] [PDF]
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L. Hertel, V. G. Lacaille, H. Strobl, E. D. Mellins, and E. S. Mocarski Susceptibility of Immature and Mature Langerhans Cell-Type Dendritic Cells to Infection and Immunomodulation by Human Cytomegalovirus J. Virol., July 1, 2003; 77(13): 7563 - 7574. [Abstract] [Full Text] [PDF]
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L. E. Gamadia, E. B. M. Remmerswaal, J. F. Weel, F. Bemelman, R. A. W. van Lier, and I. J. M. Ten Berge Primary immune responses to human CMV: a critical role for IFN-gamma -producing CD4+ T cells in protection against CMV disease Blood, April 1, 2003; 101(7): 2686 - 2692. [Abstract] [Full Text] [PDF]
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V. J. Cavanaugh, Y. Deng, M. P. Birkenbach, J. S. Slater, and A. E. Campbell Vigorous Innate and Virus-Specific Cytotoxic T-Lymphocyte Responses to Murine Cytomegalovirus in the Submaxillary Salivary Gland J. Virol., February 1, 2003; 77(3): 1703 - 1717. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
B in DCs. Immunoblotting of
nuclear NF-
) or were mock
infected (
) for 48 hours and then both groups of DCs were incubated
with influenza virus for 6 hours prior to adding them to autologous T
cells (T cell-DC ratio = 10:1) in bulk cultures, as described in
"Patients, materials, and methods." Mock-infected DCs (
) to
which influenza virus was not added served as controls to detect
nonspecific T-cell stimulation. CTL assay was carried out 7 days later
against influenza M1 peptide-pulsed autologous BLCL target
cells or unpulsed target cells. Lysis of unpulsed targets was
significantly lower by each group of T cells than that of
peptide-pulsed targets, and is not shown. Means and standard deviations
of percentage specific lysis from triplicate wells are
shown.